Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus

Byrska-Bishop, Marta; VanDorn, Daniel; Campbell, Amy E.; Betensky, Marisol; Arca, Philip R.; Yao, Yu; Gadue, Paul; Costa, Fernando Ferreira; Nemiroff, Robert J.; Blobel, Gerd A.; French, Deborah L.; Hardison, Ross C.; Weiss, Mitchell J.; Chou, Stella T.

doi:10.1172/jci75714

Cited by 68 publications

(92 citation statements)

References 73 publications

(84 reference statements)

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“…Comparison of chromatin binding signatures of GATA1 and GATA1s revealed that while GATA1s bound megakaryocytic genes normally, it bound many of its erythroid targets less efficiently than full-length GATA1 [21,22]. …”

Section: Human Gata1: One Gene But Two Isoforms Partially Different Fmentioning

confidence: 99%

“…Expression of GATA1s in GATA1-deficient hematopoietic cells also led to megakaryocyte expansion with impaired differentiation [51,52]. GATA1s was also observed to enhance megakaryopoiesis in the context of human induced pluripotent stem cells (iPSCs) with a GATA1 truncating mutation [22,51]. Germ line Gata1s truncating mutations have been found in some individuals without DS [48,53].…”

Section: Human Gata1: One Gene But Two Isoforms Partially Different Fmentioning

confidence: 99%

“…This class of mutations results in exclusive production of a NH-terminally deleted isoform of GATA1 known as GATA1s [20]. With respect to the DBA phenotype, studies have shown that Gata1s fails to occupy chromatin of erythroid target genes to the same extent as the full-length protein, likely explaining the erythroid defect [21,22]. By contrast, the mechanism by which GATA1s causing mutations contribute to DS-AMKL is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

Ling

Crispino

Zingariello

et al. 2018

Expert Review of Hematology

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Introduction: GATA1, the founding member of a family of transcription factors, plays important roles in the development of hematopoietic cells of several lineages. Although loss of GATA1 has been known to impair hematopoiesis in animal models for nearly 25 years, the link between GATA1 defects and human blood diseases has only recently been realized. Areas covered: Here the current understanding of the functions of GATA1 in normal hematopoiesis and how it is altered in disease is reviewed. GATA1 is indispensable mainly for erythroid and megakaryocyte differentiation. In erythroid cells, GATA1 regulates early stages of differentiation, and its deficiency results in apoptosis. In megakaryocytes, GATA1 controls terminal maturation and its deficiency induces proliferation. GATA1 alterations are often found in diseases involving these two lineages, such as congenital erythroid and/or megakaryocyte deficiencies, including Diamond Blackfan Anemia (DBA), and acquired neoplasms, such as acute megakaryocytic leukemia (AMKL) and the myeloproliferative neoplasms (MPNs). Expert Commentary: Since the first discovery of GATA1 mutations in AMKL, the number of diseases that are associated with impaired GATA1 function has increased to include DBA and MPNs. With respect to the latter, we are only just now appreciating the link between enhanced JAK/STAT signaling, GATA1 deficiency and disease pathogenesis.

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Section: Human Gata1: One Gene But Two Isoforms Partially Different Fmentioning

confidence: 99%

Section: Human Gata1: One Gene But Two Isoforms Partially Different Fmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

Ling

Crispino

Zingariello

et al. 2018

Expert Review of Hematology

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“…To date, data suggest that both GATA1 mutations and trisomy 21 lead to expansion of the erythromegakaryocyte compartment. 71,[74][75][76][77] How they work in concert to transform hematopoietic cells, however, remains to be determined.…”

mentioning

confidence: 99%

GATA factor mutations in hematologic disease

Crispino

Horwitz

2017

Blood

156

128

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GATA family proteins play essential roles in development of many cell types, including hematopoietic, cardiac, and endodermal lineages. The first three factors, GATAs 1, 2, and 3, are essential for normal hematopoiesis, and their mutations are responsible for a variety of blood disorders. Acquired and inherited GATA1 mutations contribute to Diamond-Blackfan anemia, acute megakaryoblastic leukemia, transient myeloproliferative disorder, and a group of related congenital dyserythropoietic anemias with thrombocytopenia. Conversely, germ line mutations in GATA2 are associated with GATA2 deficiency syndrome, whereas acquired mutations are seen in myelodysplastic syndrome, acute myeloid leukemia, and in blast crisis transformation of chronic myeloid leukemia. The fact that mutations in these genes are commonly seen in blood disorders underscores their critical roles and highlights the need to develop targeted therapies for transcription factors. This review focuses on hematopoietic disorders that are associated with mutations in two prominent GATA family members, GATA1 and GATA2.

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“…Alternative splicing provides an incompletely understood pathway to fine‐tune this transcription factor's activity during hematopoiesis. flGATA1 differs from the short isoform (GATA1s) by the presence of the 83 amino acid long N‐terminus, which activates GATA1‐driven erythropoiesis and recruits flGATA1 to a subset of megakaryocyte and erythroblast genes . Thus, GATA1 isoforms control partially overlapping but not identical transcriptional modules of erythroblast and megakaryocyte maturation.…”

Section: Discussionmentioning

confidence: 99%

A Child With Dyserythropoietic Anemia and Megakaryocyte Dysplasia Due to a Novel 5′UTRGATA1sSplice Mutation

Zucker

Temm

Czader

et al. 2015

Pediatr Blood Cancer

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We describe a child with dyserythropoietic anemia; thrombocytosis; functional platelet defect and megakaryocyte dysplasia. We show that (i) this constellation of hematopoietic abnormalities was due to a germline mutation within the 5′UTR of GATA1; (ii) the mutation impaired a 5′UTR GATA1 splicing site, promoting production of the shortened GATA1s isoform lacking the N-terminus; (iii) expression of the GATA1 N-terminus is restricted to erythroblasts and megakaryocytes in normal marrow, consistent with the patient’s abnormal erythropoiesis and megakaryopoiesis. Our findings provide insights into the clinically relevant in vivo function of the N-terminal domain of GATA1 in human hematopoiesis.

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Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus

Cited by 68 publications

References 73 publications

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

GATA factor mutations in hematologic disease

A Child With Dyserythropoietic Anemia and Megakaryocyte Dysplasia Due to a Novel 5′UTRGATA1sSplice Mutation

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